Polyallylamine polymers have found many uses in recent years as therapeutic agents. For example, polyallylamines have been reported to be effective in treating patients with elevated serum phosphate levels and hyperphosphatemia (e.g., U.S. Pat. Nos. 5,496,545 and 5,667,775). Elevated serum phosphate is often present in patients with renal insufficiency, hypoparathyroidism, acute untreated acromegaly and overmedication with therapeutics comprising phosphate salts. Polyallylamines have also found uses as bile acid sequestrants (e.g., U.S. Pat. Nos. 5,624,963, 5,703,188, 5,840,766 and 6,060,517) and for lowering uric acid levels (U.S. Pat. No. 5,985,938). Of particular note is the drug Sevelamer Hydrochloride (Sevelamer), which has been approved by the Food and Drug Administration to treat hyperphosphatemia.
The characteristic structural feature of a polyallylamine polymer is the presence of repeat units from polymerized allylamine monomer. For example, Sevelamer is a homopolymer comprising repeat units in which the amine nitrogen from the polymerized allylamine monomer is unsubstituted. The structure of the repeat unit from the Sevelamer homopolymer is shown below in Structural Formula (I):
In other polyallylamines, the amine nitrogen in the polymerized allyl monomer repeat units is substituted. Suitable substituents are described below.
To maintain potency and prevent undesired side effects, it is critically important that the ingredients in a pharmaceutical product, including the pharmacologically active ingredient, are chemically stable over extended time periods, typically for at least two years. During this time, decomposition rates must be within acceptable limits. However, amine compounds are susceptible to oxidative decomposition. For this reason, drugs containing amine functional groups are generally stored and administered in the form of a salt, typically a hydrochloride (HCl) salt, which, in most cases, is more stable than the corresponding free amine. Sevelamer, for example, is stored and administered as a salt in which about 40% of the amine groups are protonated as the hydrochloride salt (about 18% by weight of the polymer is chloride).